Pathway-Targeted Drug Meliorates Cystic Fibrosis in Mice

Sun, 02/14/2010 - 17:31 — bioquicknews

In a study that could lead to new therapeutic targets for patients with cystic fibrosis (CF), a research team from the University of California-San Diego (UCSD) School of Medicine has identified a defective signaling pathway that contributes to disease severity. The researchers reported that defective signaling for a protein called peroxisome proliferator-activated receptor-γ (PPAR-γ) accounts for a portion of disease symptoms in CF, and that correction of the defective pathway with a PPAR-γ activating drug (rosiglitazone) reduces symptoms of the disease in CF mice. The scientists also showed, in both CF mice and cells from patients with CF, that the defect in signaling for PPAR-γ results from reduced levels of prostaglandins that normally activate the receptor. "The finding of the reduced PPAR-γ activating prostaglandins in CF is exciting since it could serve as a marker to identify which patients might benefit from treatment with PPAR-γ activating drugs," said Dr. Christopher Glass, senior author of the study. CF is reportedly the most common, potentially lethal genetic disease among whites, occurring in one in 3,000 births. The disease is a multisystem condition that leads to progressive lung failure, pancreatic failure, and gastrointestinal obstruction, or blockage. Exactly how the disease process occurs has been a matter of intense scientific investigation; yet despite numerous therapeutic advances, individuals with the disease continue to endure shortened lifespans. "Someone born in the 1990s with CF is expected to live to an age of around 40," said Dr Gregory Harmon, the lead author of the current study. Former NFL quarterback Boomer Esiason (photo) has a son with CF and Mr. Esiason has been very supportive of efforts to treat and cure the disease.

"CF results from a genetic mutation in a channel, or membrane pore, that facilitates the transport of chloride and bicarbonate electrolytes from inside the cell to the spaces outside the cell," said Dr. Harmon. "Loss of the CF pore channel results in inflammation and mucus accumulation. It also results in dehydration of the cell surfaces that make up the lining spaces inside the lungs and other affected organs, such as the intestinal tract."

Working with isolated cells from CF mice and human cell lines from CF patients, Dr. Harmon and his UCSD colleagues determined that multiple genes affected by PPAR-γ showed reduced expression in CF. When the researchers treated CF mice with rosiglitazone, a thiazolidinedione drug that binds to and activates PPAR-γ, gene expression was largely normalized and survival improved. The drug also corrected part of the inflammatory process in the tissue. Deleting the PPAR-γ protein in the intestine of mice worsened the disease, leading to mucus accumulation in the intestine.

Additionally, the researchers found that activating PPAR-γ could increase bicarbonate production in the intestinal tissue by increasing the activity of bicarbonate-producing enzymes called carbonic anhydrases. "For the first time, we are able to use a drug that activates bicarbonate transport without affecting chloride transport, and see improvement in the disease," Dr. Harmon said.

Those particular results provide support for the hypothesis of experts in the field, including UCSD's Dr. Paul Quinton, that increasing bicarbonate in CF tissues could be a relevant target for future therapies. Dr. Quinton was not involved in the current research, which was reported online on February 14, 2010 in Nature Medicine.